Web Exclusives: Genetics
Gene Teams Help Govern Sleep Patterns
When Trudy Mackay told me, "Males absolutely have to take naps," a light bulb went on in my head.
My father has always napped. Throughout my childhood, he regularly came home for lunch and a 20-minute siesta. Even on his wedding day, he took a pre-ceremony snooze on the church lawn.
Mackay, a geneticist at North Carolina State University, studies the sleep patterns of pesky fruit flies. These patterns are a quantitative trait, like height or life span, that vary continuously over a range. Unlike discrete traits such as cheek dimples or tongue-rolling ability, which you either have or don't have, quantitative traits are hard to study because they're governed by many genes, each with a small effect.
To find the genetic underpinnings of the flies' sleeping habits, post-doc Susan Harbison and other members of Mackay's lab derived 40 inbred fruit fly lines from wild flies found in the Raleigh, North Carolina, area. The researchers wanted to examine the flies' sleep patterns to see if there were consistent differences between the 40 genetically distinct, inbred groups.
They placed individual flies in bunk beds—small glass tubes—and inserted them into a machine that used an infrared sensor to monitor each fly's minute-by-minute activity. Periods of inactivity lasting more than five minutes suggested the flies were snoozing. The researchers then used the data to assign each fly a sleep profile, which included both the number of naps and total time spent asleep during the day and night, as well as the level of activity while awake.
They found that the sleep habits of flies within each of the 40 inbred groups were similar, suggesting a strong genetic component. The sleep profiles, however, revealed significant differences between the groups and between males and females. On average, males snoozed more during the day and slept longer overall, but were more active while awake. The females tended to have more frequent bouts of sleep, so their sleep was more disrupted.
Intrigued by the observations, Mackay's team set out to understand how genetics could explain these differences. Rather than trying to pin down the effects of individual genes, they took a holistic approach made possible by a molecular tool called a gene chip. Gene chips are about the size of a microscope slide, yet they contain thousands of genes. Scientists use these chips to examine how gene expression patterns vary under different conditions or, as in this study, among different fly lines.
Gene chips generate massive of amounts of data, which scientists analyze with computers. In this study, computers compared the expression of close to 19,000 genes in the 40 different lines. The number of sleep related genes turned out to be 1,659—an astounding number because it represents nearly 10 percent of the fly genome.
"Sleep is critical for the survival of a species, which probably explains why so many genes are involved," says Laurie Tompkins of the National Institute of General Medical Sciences. "Sleep restores the body and energizes the brain, and it can also help an animal conserve energy and avoid attracting the attention of predators."
Given the huge number of sleep genes, Mackay suspected that they'd be organized in some way. To test this, she used computational methods that searched for similar expression patterns among the 1,659 genes. She found that the genes formed teams that behaved as though they were following the commands of a captain—their expression levels went up and down together in the various fly lines.
This team approach probably reflects the fact that biological molecules usually work in groups—as components of biochemical pathways or as part of complexes with other molecules.
"If the manager of a bakery wants to make more cakes, she needs to boost production of batter, frosting, decorations—everything that goes into a cake," says Tompkins. "It works the same way in a cell. To make more of a molecular complex, you need to ramp up production of all its components."
A closer look at the identities of the sleep genes revealed some intriguing clues about the functions of sleep. Many of the day sleep genes had metabolic roles, while a number of the night sleep genes functioned in the nervous system. Mackay says this suggests that day and night sleep serve different functions: Daytime cat naps may provide rest to the body and nighttime slumber may primarily restore the mind.
The future of Mackay's research lies in understanding how gene teams form networks that underlie quantitative traits. She has helped spearhead a collaborative, nationwide project to sequence the genomes of 192 different fruit fly lines, which will provide a rich resource for her research as well as others'. This also means sequencing each line's 180 million base pair genome—no small task.
"I think we can do it," says Mackay.